Pharmaceutical formulations comprising an AKT1 inhibitor

Abstract

Provided herein are pharmaceutical formulations of the AKT1 E17K selective inhibitor 4-((1-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile maleate.

Description

WSGR Ref. No. 62619-752.601PHARMACEUTICAL FORMULATIONS COMPRISING AN AKT1 INHIBITORCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Patent Application No. 63 / 706,449, filed on October 11, 2024; and U.S. Patent Application No. 63 / 870,432, filed on August 26, 2025, all of which are hereby incorporated by reference in their entirety.BACKGROUND OF THE INVENTION

[0002] A need exists in the art for an effective treatment of cancer and neoplastic disease.Provided herein are improved pharmaceutical formulations of the AKT1 inhibitor 4-((l-(4-(2-(2- aminopyridin-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3 -yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile maleate.SUMMARY OF THE INVENTION

[0003] One embodiment provides a pharmaceutical composition comprising 4-((l-(4-(2-(2- aminopyridin-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3 -yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile maleate and at least one pharmaceutically acceptable excipient.BRIEF DESCRIPTION OF THE DRAWINGS

[0004] The features of the invention are set forth with particularity in the appended claims. A better understanding of the features of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0005] Fig. 1 illustrates the process flow diagram for the preparation of Compound 1 tablets.

[0006] Fig. 2 provides the XRPD pattern for Formulation P2 of Compound 1 before and after formulation.

[0007] Fig. 3A, 3B, and 3C provides the AUC plots for pharmacokinetic evaluation of illustrated formulations.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0008] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

[0009] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.

[0010] The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (orWSGR Ref. No. 62619-752.601 within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range.

[0011] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0012] As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to a therapeutic benefit. The term “therapeutic benefit” is meant include eradication or amelioration of the underlying disorder being treated. Also, a “therapeutic benefit” is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made. The term "treating", as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. In some embodiments, the term “treating” includes slowing or delaying the progression of the disease or disorder to which the term is applied. Additionally, in some embodiments, the term “treating” is applied to one or more of the complications resulting from the disease or disorder to which the term is applied. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above. In some embodiments, the treatment provides a partial response. A partial response, or partial remission, is a decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment. In some embodiments, the treatment provides a complete response. A complete response, or complete remission, is the disappearance of all signs of cancer in response to treatment. In some embodiments, the treatment provides a slowing of disease progression.

[0013] The term "tumor," or “cancer” as used herein, and unless otherwise specified, refers to a neoplastic cell growth, and includes pre-cancerous and cancerous cells and tissues. Tumors usually present as a lesion or lump. As used herein, “treating” a tumor means that has one or more symptoms of the disease, such as the tumor itself, vascularization of the tumor, or other parameters by which the disease is characterized, are reduced, ameliorated, inhibited, placed in aWSGR Ref. No. 62619-752.601 state of remission, or maintained in a state of remission. “Treating” a tumor also means that one or more hallmarks of the tumor may be eliminated, reduced, or prevented by the treatment. Nonlimiting examples of such hallmarks include uncontrolled degradation of the basement membrane and proximal extracellular matrix, migration, division, and organization of the endothelial cells into new functioning capillaries, and the persistence of such functioning capillaries.

[0014] The term “refractory” or “refractory to therapy” indicates that the patients have never responded to therapy.

[0015] The term “relapsed” or “relapsed after therapy” indicates that patients, after initially responding to prior therapy, have progressive disease due to acquired resistance and / or intolerance.

[0016] The term “resistance to therapy” or “acquired resistance to therapy” indicates the patients, after initially responding to prior therapy, have progressive disease due to clinical or molecular resistance to the therapy. The acquired resistance can result from emergence of resistant mutations in the molecular target of the therapy, or in the development of physiological functions such as efflux pumps.

[0017] The phrase "therapeutically effective amount", as used herein, refers to that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other.

[0018] Other aspects, advantages, and features of the invention will become apparent from the detailed description below.AKT1 Activation and Intracellular Signaling Pathways

[0019] The serine / threonine kinase AKT (also known as protein kinase B (PKB)) is a key component of the phosphoinositide-3 -kinase (PI3K) / AKT signaling pathway, as it exerts a pivotal role in cell growth, proliferation, survival, and metabolism. Over the last few decades, the PI3K / AKT signaling pathway has been investigated intensively as dysregulated proteins within this signaling cascade behave as oncogenic drivers in various cancer types. Genomic alterations, such as deletions or mutations in tumor suppressor PTEN, PI3K, and / or AKT can result in enhanced pathway activity. These genetic alterations can lead to the hyperactivation of AKT, abnormally activating a major signaling node within the PI3K / AKT pathway.

[0020] AKT proteins play a crucial role within the PI3K / AKT pathway, modulating major cellular functions including cell cycle progression, cell size, regulation of glucose metabolism, transcription, protein synthesis, genome stability, and neovascularization. For example, AKT directly phosphorylates the tumor suppressor tuberous sclerosis 2 (TSC2) at S939 / T1462 andWSGR Ref. No. 62619-752.601 impairs its stability, leading to the release of its inhibitory effect on mTOR. In turn, activated mTOR transduces the growth factors signaling to downstream targets such as p70 ribosomal S6 kinase (S6K1) and eukaryotic translation initiation factor 4E binding protein 1, leading to increased protein translation. mTOR is a key component in the AKT signaling pathway, which is a downstream member of AKT and important regulator for cell metabolism and growth. mTOR is also an activator which can directly phosphorylate AKT’s regulatory serine residue, Ser473. mTOR forms a complex with rapamycin-insensitive companion of mTOR (RICTOR) (and other proteins) to form mTOR complex 2 (mT0RC2), which can directly phosphorylate AKT Ser473. AKT can affect cell survival and growth because it can influence the tuberous sclerosis complex (TSC) 1 / 2 along the mTORC signaling pathway and inhibit pro-apoptotic proteins or signals. In addition, AKT is able to phosphorylate and activate cAMP responsive element binding protein 1, which also plays important roles in tumorigenesis.

[0021] AKT proteins also play a role blocking apoptosis through the inactivation of pro- apoptotic proteins, and mediate cellular growth factors, promoting cell survival. AKT is also a major downstream effector of nuclear factor-kappaB (NfxB), which may link AKT signaling to the nucleus of a cell. Furthermore, AKT is a key downstream mediator of the phosphoinositide- 3-kinase (PI3K) signaling pathway. Adding to the complexity of the PI3K / AKT signaling pathway, PI3Ks can be activated by several different pathways. For example, Class I PI3Ks, PI3Ka, PI3KP, PI3Ky, and PI3K5, are activated by a cascade of activated receptor tyrosine kinase (RTK) and recruitment of growth factor receptor-bound protein 2 (GRB2), whereby GRB2 recruits the RAS family of GTPases to directly interact with and activate Class I PI3Ks. Alternatively, PI3K activation can proceed directly from interactions with RTKs or G-protein- coupled receptors (GPCRs). Consequently, the AKT cascade is activated by either RTKs or GPCRs, along with other signals including integrins, B cell receptors, T cell receptors, and cytokine receptors. Given the complexity of the AKT signaling cascade, it is unsurprising that multiple studies have shown that hyperactivation in this pathway frequently result in various cancers, such as, but not limited to, breast cancer, endometrial cancer, uterine cancer, cervical cancer, gastric carcinoma, glioblastoma, gliosarcomas, head and neck squamous cell carcinoma, ovarian cancer, pancreatic cancer, and prostate cancer, and are often associated with tumor aggressiveness (Nitulescu, G. M. et al., Int J Oncol., 2018; 53(6): 2319-2331).AKT1 Kinase

[0022] AKT is a key downstream mediator of the highly complex PI3K signaling pathway, as AKT can directly phosphorylate many proteins that are involved in diverse cellular processes, including cell proliferation, survival, migration, and metabolism.WSGR Ref. No. 62619-752.601

[0023] The complexity of this pathway is compounded by the presence of three AKT isoforms in mammals, AKT1, AKT2, and AKT3. While the isoforms are encoded by different genes, they are highly homologous at the protein level and share a conserved domain structure comprising an N-terminal pleckstrin homology (PH) domain, a kinase domain, and a C-terminal regulatory domain comprising a hydrophobic moiety, which includes the regulatory serine residue (Nitulescu, G. M. et al., Int J Oncol., 2018; 53(6): 2319-2331). Though the AKT isoforms share a high sequence homology, they differ in their intracellular, cellular, and tissue functions and localizations, resulting in a highly complex signaling pathway with over a hundred downstream substrates. Each of the 3 mammalian AKT isoforms have overlapping as well as distinct functions. For example, AKT1 is ubiquitously expressed, whereas AKT2 is primarily expressed in insulin-responsive tissues, and AKT3 is primarily expressed in brain and testes.

[0024] AKT is known as a survival kinase and mediates cell survival and proliferation by regulatory inhibition of apoptotic pathways through phosphorylation of BAD or MDM2 and regulation of Bcl2 expression. Malfunctions of AKT manifested as aberrantly increased activity typically lead to enhanced proliferation, growth, survival, and resistance to apoptosis (Alwhaibi, A. et al., Pharmacol Res., 2019, 145: 104270). For example, enhanced activation of all three AKT isoforms has been implicated in tumor development and progression, as shown in gastric, glioma, melanoma, breast, endometrial, uterine, ovarian, pancreatic, colorectal, and prostate cancers among others. Additionally, AKT1 has been found to be involved in invasion and migration of cancerous cells (Alwhaibi, A. et al., Pharmacol Res., 2019, 145: 104270). Researchers found that silencing the AKT1 isoform can abrogate specific types of cancer cell migration. However, there have been other studies which have demonstrated that activated AKT1 resulted in less metastatic propensity for lung metastatic lesion cells and breast cancer cells. AKT1 has also been identified as a key protein involved in angiogenesis, lung cancer, and tumorigenesis. These features make AKT a highly attractive target for treatment options.

[0025] Many kinase inhibitors (including AKT inhibitors) target a catalytic domain within the protein. However, the three AKT isoforms share a phosphorylation site in the catalytic domain corresponding to a threonine residue; specifically, Thr308 in AKT1, Thr309 in AKT2, and Thr305 in AKT3. The three AKT isoforms are activated by a second phosphorylation in the C- terminus of the protein at a regulatory serine residue; specifically, Ser473 in AKT1, Ser474 in AKT2, and Ser472 in AKT3. Known phosphorylating agents of AKT1 at Ser473 include, but are not limited to PDK-1, integrin-linked kinase (ILK), members of the PI3K-related kinase (PIKK) family, and mammalian target of rapamycin (mTOR) (Nitulescu, G. M. et al., Int J Oncol., 2018; 53(6): 2319-2331). The high sequence homology of the AKT isoforms has proved challenging in regard to the selectivity of AKT inhibitors, resulting in dose-limiting side effects duringWSGR Ref. No. 62619-752.601 treatment and a lack of efficacy. Thus, there remains a need to identify AKT mutant-specific and AKT isoform-selective treatment options.

[0026] The most common mutation among AKT isoforms reported across all cancers is the somatic AKT1-E17K mutation. It has been determined that the AKT1 gene mutation E17K can affect cell growth, proliferation, survival, and migration of breast cancer cells, colorectal cancer cells, and ovarian cancer cells (Chen, Y. et al., Front Cell Dev Biol., 2020; 8: 573599). These mutations in the PH structural domain increase the binding of AKT1 to Phosphatidylinositol - 3,4,5-triphosphate (PIP3) lipid ligand, which accelerates transfer of AKT from the cytoplasm to the cell membrane through direct interactions between the PH domain of AKT and the phosphatidylinositol headgroup. Transfer of AKT onto the cell membrane allows it to be further phosphorylated and activated. Once fully activated, AKT can return to the cytoplasm, or go to the nucleus, or other intracellular sites, and phosphorylate other substrate proteins to regulate cell function.

[0027] Somatic cell mutations can be a major driver in activating the PI3K-AKT signaling pathway, with the E17K mutation being the highest frequency of AKT1 mutations. This mutation is nearly exclusively present in AKT1. The AKT1 E17K mutation has been shown to mediate the PI3K-AKT signaling cascade by expanding PIP lipid specificity, which causes conformational changes. This also enhances subcellular localization to accelerate localization of the PH structural domain to the plasma membrane. Additionally, the E17K mutation increases PIP3 binding specificity by 7-fold and phosphatidylinositol-(4,5)-bisphosphate (PIP2) by 100- fold. The AKT1 E17K mutation also causes rapid conformational changes in the AKT1 PH structural domain. The conformational changes to this domain result in a 4.5-fold increase in its membrane localization, which can result in excessive phosphorylation and activation. The AKT1 E17K mutation can also result in enhanced subcellular localization by increasing the transient expression.

[0028] The AKT1 E17K mutation is a recurrent somatic cell mutation predominantly in breast cancer, uterine cancer, endometrial cancers, ovarian cancer, prostate cancer, meningioma, and in the somatic mosaic overgrowth disease Proteus syndrome. Activating mutations and overexpression of AKT has been correlated to resistance to chemotherapeutic agents such as cisplatin, methotrexate, and paclitaxel. For example, the E17K mutation enhances migration of breast cancer cells, and also enhances resistance to chemotherapeutic drugs. Given the conformational and signaling effects of the AKT1 E17K mutation, and its prevalence in various cancers, the AKT1 E17K mutation poses a useful target for the targeted treatment of cancers.WSGR Ref. No. 62619-752.601AKT1 Inhibitor

[0029] The heterocyclic AKT1 inhibitor described herein as Compound 1 refers to 4-((l-(4-(2- (2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin- 4-yl)amino)pyrimidine-2-carbonitrile maleate. The molecular structure of Compound 1 is shown below:Compound 14-((l-(4-(2-(2-aminopyri din-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile maleate

[0030] Compound 1 has been previously disclosed in PCT patent publication WO 2024 / 073371 and related patent applications and granted patents, which are incorporated by reference in their entirety. Compound 1 is a selective inhibitor of AKT1 E17K.

[0031] There is a need in the art to provide stable, bioavailable formulations of Compound 1, wherein the formulations allow administration via oral route, are stable over prolonged period of storage, is non-toxic and exhibits good bioavailability.Pharmaceutical Compositions

[0032] One embodiment provides a pharmaceutical composition comprising 4-((l-(4-(2-(2- aminopyridin-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3 -yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile maleate and at least one pharmaceutically acceptable excipient.

[0033] Another embodiment provides the pharmaceutical composition wherein the 4-((l-(4-(2- (2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin- 4-yl)amino)pyrimidine-2-carbonitrile maleate is sieved through size 30 mesh prior to compounding.

[0034] Another embodiment provides the pharmaceutical composition wherein the composition is compounded in a wet granulation process.WSGR Ref. No. 62619-752.601

[0035] Another embodiment provides the pharmaceutical composition, wherein the composition is a tablet dosage form or a capsule dosage form. Another embodiment provides the pharmaceutical composition, wherein the composition exhibits long term stability.

[0036] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity). Optimal doses are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0037] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.

[0038] One embodiment provides a pharmaceutical composition comprising 4-((l-(4-(2-(2- aminopyridin-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3 -yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile maleate and at least one pharmaceutically acceptable excipient.

[0039] In some embodiments, the 4-((l-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)- 3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile maleate is sieved through size 30 mesh prior to compounding.

[0040] In some embodiments, the composition is compounded in a wet granulation process.

[0041] In some embodiments, at least one excipient is a filler.

[0042] In some embodiments, the filler is selected from microcrystalline cellulose, mannitol, starch, powdered sucrose, powdered cellulose, dextrin, lactose, or calcium sulfate.

[0043] In some embodiments, the filler is selected from microcrystalline cellulose or mannitol.

[0044] In some embodiments, the filler is a combination of microcrystalline cellulose and mannitol.

[0045] In some embodiments, at least one excipient is a binder.

[0046] In some embodiments, the binder is selected from hydroxypropyl cellulose (HPC), microcrystalline cellulose, starch, lactose, a sugar alcohol, isomalt, polyvinylpyrrolidone (PVP) or polyethylene glycol (PEG).

[0047] In some embodiments, the binder is hydroxypropyl cellulose (HPC).WSGR Ref. No. 62619-752.601

[0048] In some embodiments, the hydroxypropyl cellulose has a weight average molecular weight of about 40,000 to about 95,000; or about 80,000.

[0049] In some embodiments, at least one excipient is a disintegrant.

[0050] In some embodiments, the disintegrant is selected from cross-linked polyvinylpyrrolidone, crosslinked sodium carboxymethyl cellulose, starch or sodium starch glycolate.

[0051] In some embodiments, the disintegrant is crosslinked sodium carboxymethyl cellulose.

[0052] In some embodiments, at least one excipient is a lubricant.

[0053] In some embodiments, the lubricant is magnesium stearate.

[0054] In some embodiments, the 4-((l-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)- 3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile maleate is present in about 25% (w / w) to about 40% (w / w).

[0055] In some embodiments, the 4-((l-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)- 3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile maleate is present in about 29% (w / w) to about 31% (w / w).

[0056] In some embodiments, the at least one excipient is a filler present in an amount of about 50% (w / w) to about 70% (w / w).

[0057] In some embodiments, the filler is present in an amount of about 55% (w / w) to about 65% (w / w).

[0058] In some embodiments, the filler is present in an amount of about 55% (w / w) to about 65% (w / w).

[0059] In some embodiments, the at least one excipient is a binder present in an amount of about 1% (w / w) to about 5% (w / w).

[0060] In some embodiments, the binder is present in the amount of about 2% (w / w) to about 4% (w / w).

[0061] In some embodiments, the binder is present in an amount of about 2% (w / w) to about 4% (w / w).

[0062] In some embodiments, the composition exhibits long term stability.

[0063] In some embodiments, the composition exhibits no change in polymorph form of 4-((l- (4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyri din-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile maleate during compounding.Methods of Treatment

[0064] One embodiment provides a method of treating a cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising 4-((l-(4-(2-(2- aminopyridin-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-WSGR Ref. No. 62619-752.601 yl)amino)pyrimidine-2-carbonitrile maleate and at least one pharmaceutically acceptable excipient.

[0065] One embodiment provides a method of treating a cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising 4-((l-(4-(2-(2-aminopyridin-3-yl)-5-(5-fluoropyridin-2-yl)-3H- imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile maleate and at least one pharmaceutically acceptable excipient.

[0066] One embodiment provides a method of treating a cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition as described herein.

[0067] One embodiment provides a method of treating a cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition as described herein.

[0068] In some embodiments, the cancer is breast cancer.

[0069] In some embodiments, the cancer is a hormone receptor positive (HR+) breast cancer.

[0070] In some embodiments, the cancer is a human epidermal growth factor receptor 2 negative (HER2-) breast cancer.

[0071] In some embodiments, the cancer is a HR+ / HER2- breast cancer.

[0072] In some embodiments, the cancer is a HR+ / HER2-low breast cancer.

[0073] In some embodiments, the cancer is a HR+ / HER2+ breast cancer.

[0074] In some embodiments, the cancer is a triple negative breast cancer (TNBC).

[0075] In some embodiments, the cancer is an invasive breast cancer.

[0076] In some embodiments, the cancer is uterine cancer.

[0077] In some embodiments, the cancer is uterine sarcoma.

[0078] In some embodiments, the cancer is endometrial cancer.

[0079] In some embodiments, the cancer is Type I endometrial cancer.

[0080] In some embodiments, the cancer is Type II endometrial cancer.

[0081] In some embodiments, the cancer is Type II endometrial papillary serous carcinoma.

[0082] In some embodiments, the cancer is Type II endometrial clear cell carcinoma.

[0083] In some embodiments, the cancer is Type II endometrial undifferentiated carcinoma.

[0084] In some embodiments, the cancer is Type II endometrioid carcinoma.

[0085] In some embodiments, the cancer is microsatellite instability (MSI) high and / or DNA mismatch repair (MMR) deficient.

[0086] In some embodiments, the cancer is tumor mutational burden (TMB) high.

[0087] In some embodiments, the cancer is HER2-.

[0088] In some embodiments, the cancer is cervical cancer.WSGR Ref. No. 62619-752.601

[0089] In some embodiments, the cancer is a cervical squamous cell carcinoma.

[0090] In some embodiments, the cancer is a cervical adenocarcinoma.

[0091] In some embodiments, the cancer is prostate cancer.

[0092] In some embodiments, the cancer is prostate adenocarcinoma.

[0093] In some embodiments, the cancer is prostate neuroendocrine cancer.

[0094] In some embodiments, the cancer is prostate small cell neuroendocrine cancer.

[0095] In some embodiments, the cancer is prostate large cell carcinoma.

[0096] In some embodiments, the cancer is prostate transitional cell carcinoma.

[0097] In some embodiments, the cancer is prostate sarcoma.

[0098] In some embodiments, the cancer is bladder cancer.

[0099] In some embodiments, the cancer is urothelial cancer.

[0100] In some embodiments, the cancer is squamous cell cancer of the bladder.[0010.1] In some embodiments, the cancer is small cell cancer of the bladder.

[0102] In some embodiments, the cancer is adenocarcinoma of the bladder.

[0103] In some embodiments, the cancer is lung cancer.

[0104] In some embodiments, the cancer is non-small cell lung cancer.

[0105] In some embodiments, the cancer is non-squamous non-small cell lung cancer.

[0106] In some embodiments, the cancer is squamous non-small cell lung cancer.

[0107] In some embodiments, the cancer is colon cancer.

[0108] In some embodiments, the cancer is anal cancer.

[0109] In some embodiments, the cancer is a meningioma.

[0110] In some embodiments, the cancer is a glioma.

[0111] In some embodiments, the cancer is pancreatic cancer.

[0112] In some embodiments, the cancer is exocrine pancreatic cancer.

[0113] In some embodiments, the cancer is neuroendocrine pancreatic cancer.

[0114] In some embodiments, the cancer is thyroid cancer.

[0115] In some embodiments, the cancer is myxofibrosarcoma.

[0116] In some embodiments, the cancer is parotid gland cancer.

[0117] In some embodiments, the cancer is esophageal cancer.

[0118] In some embodiments, the cancer is stomach cancer.

[0119] In some embodiments, the cancer is skin cancer.

[0120] In some embodiments, the cancer is nonmelanoma skin cancer.

[0121] In some embodiments, the cancer is squamous nonmelanoma skin cancer.

[0122] In some embodiments, the cancer is non-squamous nonmelanoma skin cancer.

[0123] In some embodiments, the cancer is ovarian cancer.WSGR Ref. No. 62619-752.601

[0124] In some embodiments, the cancer is epithelial ovarian cancer.

[0125] In some embodiments, the cancer is serous epithelial ovarian cancer.

[0016] In some embodiments, the cancer is endometrioid ovarian cancer.

[0127] In some embodiments, the cancer is clear cell ovarian cancer.

[0128] In some embodiments, the cancer is mucinous ovarian cancer.

[0129] In some embodiments, the cancer is adenoid cystic carcinoma.

[0130] In some embodiments, the cancer is renal cell cancer.

[0131] In some embodiments, the cancer is appendix cancer.

[0132] In some embodiments, the cancer is multiple myeloma.

[0133] In some embodiments, the cancer is acute myeloid leukemia.

[0134] In some embodiments, the cancer is cancer of unknown primary.

[0135] In some embodiments, the cancer is locally advanced.

[0136] In some embodiments, the cancer is metastatic.

[0137] In some embodiments, the method is adjuvant therapy following surgical resection.

[0138] In some embodiments, the method is neo-adjuvant therapy.

[0139] In some embodiments, the method is first-line systemic therapy for locally advanced or metastatic disease.

[0140] In some embodiments, the patient has relapsed after prior therapy.

[0141] In some embodiments, the patient has acquired resistance to prior therapy.

[0142] In some embodiments, the patient is refractory to therapy.

[0143] In some embodiments, the patient has shown progression on at least one CDK4 / 6 inhibitor.

[0144] In some embodiments, the patient has shown progression on at least one endocrinebased regimen.

[0145] In some embodiments, the patient has shown progression on cytotoxic chemotherapy.

[0146] In some embodiments, the cancer is characterized by existence of AKT1-E17K mutation.

[0147] In some embodiments, the cancer exhibits one or more co-occurring alterations selected from a PIK3CA alteration, a PIK3R1 alteration, an AKT1 alteration, and PTEN alteration.

[0148] In some embodiments, the patient exhibits risk factors for hyperglycemia.

[0149] In some embodiments, the patient exhibits risk factors selected from obesity, body mass index greater than or equal to 30, fasting blood glucose over 160 mg / dL, HbAlc greater than 6.0.WSGR Ref. No. 62619-752.601

[0150] In some embodiments, the patient exhibits Type I diabetes, diabetes requiring insulin, diabetes requiring metformin or another oral hypoglycemic agent, or pre-diabetes treated with metformin or another oral hypoglycemic agent.EXAMPLES

[0151] The present disclosure is further illustrated by the following examples, which should not be construed as limiting in any way. The experimental procedures to generate the data shown are discussed in more detail below. The disclosure has been described in an illustrative manner, and it is to be understood that the terminology used is intended to be in the nature of description rather than of limitation.Overview

[0152] Three dose strengths, 25 mg, 50 mg, and 200 mg of Compound 1 tablets were developed. The major manufacturing process of Compound 1 tablets consists of common granulation (wet granulation), compression and coating. The flow chart for manufacturing process refer to Figure 1. Six prototype batches were produced to assess feasibility of Compound 1 Tablets. Two lead prototype formulation was selected for an in vivo pharmacokinetic (PK) and short-time accelerated stability study.Prototype Tablet Formulation and Process Development

[0153] The purpose was to develop a robust formulation and process for Compound 1 tablets that met early phase clinical manufacturing requirement. Common granules were preferred for Compound 1 tablets 25 mg, 50 mg, and 200 mg strengths. Both dry granulation and wet granulation were explored during prototype development, but sticking was observed during roller compaction (RC) process, not recommended to move forward. XRPD results showed that no API crystal transformation occurred during wet granulation, therefore wet granulation was selected to move forward. API agglomeration was observed in prototypes development, Compound 1 sieved with 30 mesh screen before wet granulation to reduce the its impact on the process and product quality. Six prototype batches containing dry granulation / wet granulation, different drug load, with or without extra Microcrystalline Cellulose PH-102 were prepared and tested to assess feasibility of Compound 1 tablets. The formulations of these prototypes were summarized in Table 1.WSGRRef. No. 62619-752.601Table 1WSGR Ref. No. 62619-752.601*Compound 1 sieved with 30 mesh screen.WSGR Ref. No. 62619-752.601

[0154] For batches of dry granulation, the major processes of Compound 1 tablet production consist of pre-blending, roller compaction, blending / lubrication and tablet compression, refer to the steps shown below:1. Pre-blending was started with mixing Colloidal Silica Dioxide Aerosil 200 Pharma with Microcrystalline Cellulose PH-102 manually, then adding the mixture into Compound 1 bag and mix manually. The mixture was then co-sieve with a 30 mesh screen, followed by adding into the suitable container. The Mannitol 100SD, Hydroxypropyl Cellulose Klucel EXF and Croscarmellose Sodium SD-711 was sieved and mixed with a 30 mesh screen. The resulting mixture was used to rinse the Compound 1 bag, then added into the above container for mixing. The Magnesium Stearate LIGAMED MF-2-V-MB was sieved with a 60 mesh screen, then added into the container for pre-blending.2. The pre-blend was proceeded to roller compaction on TFC-LAB Micro. During the roller compaction process, ribbons were screened through a granulation screen to produce granules. The granules were then mixed with extra-granular excipients. The amount of extra excipients was adjusted based on the yield of intra granules. Extra Microcrystalline Cellulose PH-102 was sieved using a 30 mesh screen and extra Magnesium Stearate LIGAMED MF-2-V-MB was sieved using a 60 mesh screen before blending and lubrication. Sieved Microcrystalline Cellulose PH-102 was added to the intra granules for blending, followed by the Magnesium Stearate LIGAMED MF-2-V-MB for lubrication.3. The blend was then compressed into tablets using a rotary tablet press such as Korsch XL100.

[0155] For batches of wet granulation, the major processes of Compound 1 tablets production consist of wet granulation, blending / lubrication and tablet compression, refer to the steps shown below:1. Compound 1 was sieved by 30 mesh screen, sieved Compound 1 and intra excipients were charged into the high shear bowl. Then, purified water was added to granulate the excipients with Compound 1 while applying high shear. After adding purified water, wet massing was applied to further strengthening the granules.2. The wet granules were unloaded from the high shear bowl, and passed through a Comil U5 using a 156Q (3962 pm) screen to ensure that large granules were broken into smaller granules to be efficiently dried in the next step.3. The wet milled granules were then loaded into oven tray dryer until a certain loss on drying value was reached.4. The dried granules were then milled using a Comil U5 equipped with a 062G (1575 pm) screen.5. The amount of extra excipients was adjusted based on the yield of intra granules. Extra Microcrystalline Cellulose PH-102 was sieved using a 30 mesh screen and extra Magnesium Stearate LIGAMED MF-2-V-MB was sieved using a 60 mesh screen before blending and lubrication. Sieved Microcrystalline Cellulose PH-102 was added to the intra granules for blending, the Magnesium Stearate LIGAMED MF-2-V-MB for lubrication.WSGR Ref. No. 62619-752.6016. The blend was then compressed into tablets using a rotary tablet press such as Korsch XL100.

[0156] XRPD results of intra-granules under wet granulation is showed in Figure 2, XRPD results shows main peaks of API and intra-granule are comparable.Tablet Accelerated Stability Study

[0157] Prototype formulations of P5 and P6 were entered into accelerated stability program to help select the lead formulation. Compound 1 Tablets 200 mg were packaged into Pharm Bottle 60CC, Pharm Cap 33MM and foil induction seal. The accelerated stability tablets were tested after 2 W and 4 W for appearance, assay and impurities, water content and dissolution. The accelerated stability data for P5 is showed in Table 2. The accelerated stability data for P6 is showed in Table 3.WSGRRef. No.62619-752.601Table 2WSGR Ref. No. 62619-752.601Table 3Tablet Pharmacokinetic Study

[0158] In order to compare the effects of drug load on the in vivo pharmacokinetics of prototype tablets, Compound 1 Tablets 200 mg of accelerated stability batch P5 and P6 were subject to PK analysis. The results are shown in Table 4, Figure 8, Figure 9 and Figure 10.WSGR Ref. No. 62619-752.601Table 4Conclusion1. For dry granulation, sticking was observed during roller compaction, not recommended to move forward. XRPD results showed that no API crystal transformation occurred during wet granulation, therefore, wet granulation was selected to move forward, but still need to keep monitoring if there is sticking issue.2. Extra 10% MCC PHI 02 did not significantly improve the compressibility of the blend, and core tablet appearance is not as good as without extra MCC PHI 02. Therefore, P5 and P6 (without extra MCC PHI 02) were selected for accelerated stability and PK study.3. All prototypes tablets showed quick dissolution.4. Accelerated stability study of P5 and P6 showed that assay, water content, impurity and dissolution had no significant change during 4W study at 40±2°C / 75±5% RH conditions.5. PK study results showed that 25% DL (P6) had better effects than 33.33% DL (P5) of in-vivo pharmacokinetics, so P6 (25% DL) was selected for demo batch.Wet Milling Procedure for Compound 1 on Kilogram ScaleTable 5WSGRRef. No.62619-752.601WSGR Ref. No. 62619-752.601

[0159] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

WSGR Ref. No. 62619-752.601CLAIMSWe claim:

1. A pharmaceutical composition comprising 4-((l-(4-(2-(2-aminopyridin-3-yl)-5-(5- fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile maleate and at least one pharmaceutically acceptable excipient.

2. The pharmaceutical composition of claim 1, wherein the 4-((l-(4-(2-(2-aminopyridin-3-yl)- 5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile maleate is sieved through size 30 mesh prior to compounding.

3. The pharmaceutical composition of claim 1 or 2, wherein the composition is compounded in a wet granulation process.

4. The pharmaceutical composition of any one of claims 1-3, wherein at least one excipient is a filler.

5. The pharmaceutical composition of claim 4, wherein the filler is selected from microcrystalline cellulose, mannitol, starch, powdered sucrose, powdered cellulose, dextrin, lactose, or calcium sulfate.

6. The pharmaceutical composition of claim 5, wherein the filler is selected from microcrystalline cellulose or mannitol.

7. The pharmaceutical composition of claim 5, wherein the filler is a combination of microcrystalline cellulose and mannitol.

8. The pharmaceutical composition of any one of claims 1-7, wherein at least one excipient is a binder.

9. The pharmaceutical composition of claim 8, wherein the binder is selected from hydroxypropyl cellulose (HPC), microcrystalline cellulose, starch, lactose, a sugar alcohol, isomalt, polyvinylpyrrolidone (PVP) or polyethylene glycol (PEG).

10. The pharmaceutical composition of claim 9, wherein the binder is hydroxypropyl cellulose (HPC).

11. The pharmaceutical composition of claim 10, wherein the hydroxypropyl cellulose has a weight average molecular weight of about 40,000 to about 95,000; or about 80,000.

12. The pharmaceutical composition of any one of claims 1-11, wherein at least one excipient is a disintegrant.

13. The pharmaceutical composition of claim 12, wherein the disintegrant is selected from cross-linked polyvinylpyrrolidone, crosslinked sodium carboxymethyl cellulose, starch or sodium starch glycolate.WSGR Ref. No. 62619-752.60114. The pharmaceutical composition of claim 13, wherein the disintegrant is crosslinked sodium carboxymethyl cellulose.

15. The pharmaceutical composition of any one of claims 1-14, wherein at least one excipient is a lubricant.

16. The pharmaceutical composition of claim 15, wherein the lubricant is magnesium stearate.

17. The pharmaceutical composition of any one of claims 1-16, wherein the 4-((l-(4-(2-(2- aminopyridin-3-yl)-5-(5-fluoropyri din-2 -yl)-3H-imidazo[4,5-b]pyri din-3- yl)benzyl)piperidin-4-yl)amino)pyrimidine-2-carbonitrile maleate is present in about 25% (w / w) to about 40% (w / w).

18. The pharmaceutical composition of claim 17, wherein the 4-((l-(4-(2-(2-aminopyridin-3- yl)-5-(5-fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile maleate is present in about 29% (w / w) to about 31% (w / w).

19. The pharmaceutical composition of any one of claims 1-18, wherein the at least one excipient is a filler present in an amount of about 50% (w / w) to about 70% (w / w).

20. The pharmaceutical composition of claim 19, wherein the filler is present in an amount of about 55% (w / w) to about 65% (w / w).

21. The pharmaceutical composition of claim 6 or 7, wherein the filler is present in an amount of about 55% (w / w) to about 65% (w / w).

22. The pharmaceutical composition of any one of claims 1-21, wherein the at least one excipient is a binder present in an amount of about 1% (w / w) to about 5% (w / w).

23. The pharmaceutical composition of claim 22, wherein the binder is present in the amount of about 2% (w / w) to about 4% (w / w).

24. The pharmaceutical composition of claim 10 or 11, wherein the binder is present in an amount of about 2% (w / w) to about 4% (w / w).

25. The pharmaceutical composition of any one of claims 1-24, wherein the composition exhibits long term stability.

26. The pharmaceutical composition of any one of claims 1-24, wherein the composition exhibits no change in polymorph form of 4-((l-(4-(2-(2-aminopyridin-3-yl)-5-(5- fluoropyridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzyl)piperidin-4- yl)amino)pyrimidine-2-carbonitrile maleate during compounding.

27. A method of treating a cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition of any one of claims 1-26.WSGR Ref. No. 62619-752.60128. A method of treating a cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition of any one of claims 1-26.

29. The method of claim 27 or 28, wherein the cancer is breast cancer.

30. The method of claim 29, wherein the cancer is a hormone receptor positive (HR+) breast cancer.

31. The method of claim 29, wherein the cancer is a human epidermal growth factor receptor 2 negative (HER2-) breast cancer.

32. The method of claim 29, wherein the cancer is a HR+ / HER2- breast cancer.

33. The method of claim 29, wherein the cancer is a HR+ / HER2-low breast cancer.

34. The method of claim 29, wherein the cancer is a HR+ / HER2+ breast cancer.

35. The method of claim 29, wherein the cancer is a triple negative breast cancer (TNBC).

36. The method of claim 29, wherein the cancer is an invasive breast cancer.

37. The method of claim 27 or 28, wherein the cancer is uterine cancer.

38. The method of claim 37, wherein the cancer is uterine sarcoma.

39. The method of claim 37, wherein the cancer is endometrial cancer.

40. The method of claim 37, wherein the cancer is Type I endometrial cancer.

41. The method of claim 37, wherein the cancer is Type II endometrial cancer.

42. The method of claim 41, wherein the cancer is Type II endometrial papillary serous carcinoma.

43. The method of claim 41, wherein the cancer is Type II endometrial clear cell carcinoma.

44. The method of claim 41, wherein the cancer is Type II endometrial undifferentiated carcinoma.

45. The method of claim 41, wherein the cancer is Type II endometrioid carcinoma.

46. The method of claim 37, wherein the cancer is microsatellite instability (MSI) high and / or DNA mismatch repair (MMR) deficient.

47. The method of claim 37, wherein the cancer is tumor mutational burden (TMB) high.

48. The method of claim 37 wherein the cancer is HER2-.

49. The method of claim 27 or 28, wherein the cancer is cervical cancer.

50. The method of claim 49, wherein the cancer is a cervical squamous cell carcinoma.

51. The method of claim 49, wherein the cancer is a cervical adenocarcinoma.

52. The method of claim 27 or 28, wherein the cancer is prostate cancer.

53. The method of claim 52, wherein the cancer is prostate adenocarcinoma.

54. The method of claim 52, wherein the cancer is prostate neuroendocrine cancer.

55. The method of claim 52, wherein the cancer is prostate small cell neuroendocrine cancer.WSGR Ref. No. 62619-752.60156. The method of claim 52, wherein the cancer is prostate large cell carcinoma.

57. The method of claim 52, wherein the cancer is prostate transitional cell carcinoma.

58. The method of claim 52, wherein the cancer is prostate sarcoma.

59. The method of claim 27 or 28, wherein the cancer is bladder cancer.

60. The method of claim 59, wherein the cancer is urothelial cancer.

61. The method of claim 59, wherein the cancer is squamous cell cancer of the bladder.

62. The method of claim 59, wherein the cancer is small cell cancer of the bladder.

63. The method of claim 59, wherein the cancer is adenocarcinoma of the bladder.

64. The method of claim 27 or 28, wherein the cancer is lung cancer.

65. The method of claim 27 or 28, wherein the cancer is non-small cell lung cancer.

66. The method of claim 27 or 28, wherein the cancer is non-squamous non-small cell lung cancer.

67. The method of claim 27 or 28, wherein the cancer is squamous non-small cell lung cancer.

68. The method of claim 27 or 28, wherein the cancer is colon cancer.

69. The method of claim 27 or 28, wherein the cancer is anal cancer.

70. The method of claim 27 or 28, wherein the cancer is a meningioma.

71. The method of claim 27 or 28, wherein the cancer is a glioma.

72. The method of claim 27 or 28, wherein the cancer is pancreatic cancer.

73. The method of claim 72, wherein the cancer is exocrine pancreatic cancer.

74. The method of claim 72, wherein the cancer is neuroendocrine pancreatic cancer.

75. The method of claim 27 or 28, wherein the cancer is thyroid cancer.

76. The method of claim 27 or 28, wherein the cancer is myxofibrosarcoma.

77. The method of claim 27 or 28, wherein the cancer is parotid gland cancer.

78. The method of claim 27 or 28, wherein the cancer is esophageal cancer.

79. The method of claim 27 or 28, wherein the cancer is stomach cancer.

80. The method of claim 27 or 28, wherein the cancer is skin cancer.

81. The method of claim 80, wherein the cancer is nonmelanoma skin cancer.

82. The method of claim 80, wherein the cancer is squamous nonmelanoma skin cancer.

83. The method of claim 80, wherein the cancer is non-squamous nonmelanoma skin cancer.

84. The method of claim 27 or 28, wherein the cancer is ovarian cancer.

85. The method of claim 84, wherein the cancer is epithelial ovarian cancer.

86. The method of claim 84, wherein the cancer is serous epithelial ovarian cancer.

87. The method of claim 84, wherein the cancer is endometrioid ovarian cancer.

88. The method of claim 84, wherein the cancer is clear cell ovarian cancer.

89. The method of claim 84, wherein the cancer is mucinous ovarian cancer.WSGR Ref. No. 62619-752.60190. The method of claim 27 or 28, wherein the cancer is adenoid cystic carcinoma.

91. The method of claim 27 or 28, wherein the cancer is renal cell cancer.

92. The method of claim 27 or 28, wherein the cancer is appendix cancer.

93. The method of claim 27 or 28, wherein the cancer is multiple myeloma.

94. The method of claim 27 or 28, wherein the cancer is acute myeloid leukemia.

95. The method of claim 27 or 28, wherein the cancer is cancer of unknown primary.

96. The method of claim 27 or 28, wherein the cancer is locally advanced.

97. The method of any one of claims 27-96, wherein the cancer is metastatic.

98. The method of any one of claims 27-97, wherein the method is adjuvant therapy following surgical resection.

99. The method of any one of claims 27-98, wherein the method is neo-adjuvant therapy.

100. The method of any one of claims 27-99, wherein the method is first-line systemic therapy for locally advanced or metastatic disease.

101. The method of any one of claims 27-100, wherein the patient has relapsed after prior therapy.

102. The method of any one of claims 27-101, wherein the patient has acquired resistance to prior therapy.

103. The method of any one of claims 27-102, wherein the patient is refractory to therapy.

104. The method of any one of claims 29-36, wherein the patient has shown progression on at least one CDK4 / 6 inhibitor.

105. The method of any one of claims 29-36, wherein the patient has shown progression on at least one endocrine-based regimen.

106. The method of any one of claims 27-105, wherein the patient has shown progression on cytotoxic chemotherapy.

107. The method of any one of claims 27-106, wherein the cancer is characterized by existence of AKT1-E17K mutation.

108. The method of any one of claims 27-107, wherein the cancer exhibits one or more cooccurring alterations selected from a PIK3CA alteration, a PIK3R1 alteration, an AKT1 alteration, and PTEN alteration.

109. The method of any one of claims 27-108, wherein the patient exhibits risk factors for hyperglycemia.

110. The method of any one of claims 27-109, wherein the patient exhibits risk factors selected from obesity, body mass index greater than or equal to 30, fasting blood glucose over 160 mg / dL, Elb Ale greater than 6.0.WSGR Ref. No. 62619-752.601111. The method of any one of claims 27-109, wherein the patient exhibits Type I diabetes, diabetes requiring insulin, diabetes requiring metformin or another oral hypoglycemic agent, or pre-diabetes treated with metformin or another oral hypoglycemic agent.

Images